APPLICANT'S ABSTRACT: The investigation proposed herein focuses on the design, synthesis, and evaluation of novel acyclic phosphonate nucleotide analogs as antiviral/anti- HIV agents for treatment of the AIDS and drug addicted AIDS patients. Specifically, the investigation seeks to exploit recent observation that a group of acyclic phosphonate nucleotides exhibited remarkable anti-HIV/antiviral activity in vitro (IC50 0.13 microM). Several design considerations indicate that it might be possible to evolve new and synthetically readily accessible acyclic nucleotide analogs as potential antiviral agents for the treatment of AIDS by (a) modifying the acyclo tail of phosphonate thymine and uracil nucleotides, (b) substituting the phenylthio or phenylselenenyl group at the C-6 position of the uracil nucleus, and (c) substituting selective halo, alkyl and aryl substituents at the C-5 position of the uracil nucleus. Adequate quantities of these compounds will be synthesized to make them available for testing against AIDS virus. The approaches to be employed in this proposal include, the development of synthetic methologies, their characterization by NMR, mass spectrum, UV, and other spectroscopic techniques. Proposed compounds will be evaluated with respect to (1) ability to inhibit the replication of HIV-1 virus, (2) toxicity, and (3) cross-sensitivity patterns to AZT- resistant strain in cell culture through collaborative arrangements with Dr. Krishna C. Agrawal at Tulane University Medical Center, New Orleans, Louisiana 70112. This local arrangement of biological testing will allow maximum efficiency in the attainment of the most effective chemical modification of acyclic unsaturated nucleotide analogs by rapidly translating the biological observations into the design of improved anti-HIV compounds.